ABSTRACT Obesity-associated asthma is increasingly prevalent and presents as severe disease that is very difficult to treat. Obese asthma exists as phenotypes termed ?inherent? (a consequence of weight) and ?allergic? (made worse by obesity), both of which can be effectively modeled in mice. Oxidative stress is increased in obese asthmatics and may be a target for therapeutic intervention. While weight loss and its associated mobilization of fatty acids from adipose tissue has salutary effects on symptoms and objective disease, lifestyle alterations, bariatric surgery, and biological therapeutics have issues including poor long-term compliance, a lack of desirability, and high cost that limit their success as treatments for obese asthma. During weight loss, fatty acids mobilized from adipose tissue are subsequently catabolized in the liver to the ketone bodies acetoacetate (AcAc) and ?-hydroxybutyrate (BHB). Ketone bodies function as antioxidants, provide an energy source that makes cells less reliant on glycolysis, and exert anti-inflammatory effects. Based on our published and preliminary data, we hypothesize that therapeutic augmentation of ketone body concentrations in the circulation will elicit improvements in obese inherent and allergic asthma through decreasing cellular redox stress and inhibiting pro-inflammatory cytokine production. In SA1, to ascertain whether and which ketone bodies afford protection against the major aspects of obese inherent asthma, we will employ mouse models of diet-induced obesity and two genetic models of obesity accompanied by dietary or pharmacological augmentation of circulating ketone bodies accomplished by feeding a low-fat diet or a ketogenic diet, or administration of ketone bodies (BHB and AcAc), an agent that promotes ketone body formation (1,3- butanediol), or ketone ester. Measured outcomes include methacholine responsiveness, airway inflammation, lung histology, serum cytokines, and immunophenotyping. In SA2, to evaluate the impact of in vivo ketone body modulation on the pathophysiological manifestations of obese allergic asthma, we will expose the diet- or genetically-induced mouse obesity models to chronic inhalational house dust mite allergen exposure accompanied by dietary or pharmacological augmentation of circulating ketone bodies during the asthma exacerbation phase. Outcomes to be measured include methacholine responsiveness, airway inflammation, immunophenotyping, and lung remodeling. In SA3, to investigate the mechanisms of ketone body actions, we will stimulate primary airway epithelial cell and leukocyte cultures from lean and obese, non-allergic and HDM- allergic mice, in the absence and presence of ketone bodies in vitro, as well as examine tissues and cells from mice treated in SA1 and SA2. We will assess whether the intrinsic differences in cytokine secretion, glycolysis, mitochondrial oxidative stress, and endoplasmic reticulum stress between cells from lean and obese mice are modulated by ketone bodies and examine candidate receptors for these effects.